Functional architecture of the pancreatic islets: First responder cells drive the first-phase response

Abstract

Insulin-secreting {beta}-cells are functionally heterogeneous. Whether there exist cells driving the first-phase calcium response in individual islets, has not been examined. We examine first responder cells, defined by the earliest [Ca2+] response during first-phase [Ca2+] elevation, distinct from previously identified "hub" and "leader" cells. First responder cells showed characteristics of high membrane excitability and lower electrical coupling to their neighbors. The first-phase response time of {beta}-cells in the islet was spatially organized, dependent on the cells distance to the first responder cell, and consistent over time up to [~]24 h. When first responder cells were laser ablated, the first-phase [Ca2+] was slowed down, diminished, and discoordinated compared to random cell ablation. Cells that were next earliest to respond often took over the role of the first responder upon ablation. In summary, we discover and characterize a distinct first responder {beta}-cell state, critical for the islet first-phase response to glucose.